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Key aspects of our phase I gene therapy trial for haemophilia B 1. Vector pseudotyped with AAV8 capsid Seroprevalence of AAV8 in humans is lower than AAV2 3. Vector administered in the peripheral circulation A simple mode of vector delivery that takes advantage of the strong tropism of AAV8 for the liver, the native site for FIX synthesis LP1 co hFIX LP Self complementary vectors to improve potency using an expression cassette which contained a small liver specific promoter and codon optimised hFIX cDNA scAAV-LP1-hFIXco

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High vector dose Off prophylaxis for >36 months. Not required any FIX treatment 60mg 0 Pred Plasma FIX levels, Subject 6: 2x10 12 vg/kg FIX conc usage "I have not needed any of my normal treatment, either preventative or on-demand as a result of an injury. Previously, I used to infuse at home three times a week.... I play football, run and take part in triathlons - and previously I might have had to infuse both before I took part and possibly after as well. Not having to do that has been absolutely brilliant."

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Second arm: Expansion of the high dose cohort Questions: – Will perturbation of liver enzymes occur in all subjects treated at the high dose level? – Will early treatment with steroids reduce the level of transaminitis and preserve stable expression of hFIX? – Should all high dose subjects receive prophylactic steroids and if so when should this be started and for how long? 4 new subjects recruited over the last 12 months

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Summary:1 In total 10 subjects received scAAV8-LP1- hFIXco Evidence of vector mediated human FIX expression in all 10 subjects treated to date – Level of transgenic FIX achieved is dose dependent with an average of 5% of normal at the high vector dose – Expression has remained remarkable stable over time with follow-up between months – 5/7 able to stop prophylaxis, with significant improvement in quality of life and reduction in frequency of bleeding episodes Net saving to the UK government from decrease in FIX usage is >£1.5M

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Summary:2 Perturbation of liver enzymes has been observed in 4/6 subjects treated at the high dose level Not related to pre-treatment anti-AAV IgG levels Not related to HLA Not related to previous infection or treatment for HBC –?use steroids prophylactically between 7-9 weeks after gene transfer These results are encouraging and support further evaluation of the AAV approachThese results are encouraging and support further evaluation of the AAV approach